A single catalyst that can site- and chemoselectively functionalize all C(sp3)-H bond types stands to revolutionize the synthesis and diversification of organic molecules. An inherent challenge exists in developing small molecule catalysts that can functionalize inert C(sp3)-H bonds while tolerating more reactive π-functionality.
The direct functionalization of C—H bonds by transition metal catalysts is shifting the synthetic paradigm for the construction and diversification of organic molecules. However, a profound challenge lies in the development of catalysts that are reactive enough to cleave inert C—H bonds while remaining tolerant of more readily oxidizable functional groups. In particular, small molecule catalysts have demonstrated the ability to support high valent metal-heteroatom species (i.e. oxos and nitrenes) that are capable of preparative, site-selective, and stereospecific oxidation of inert C—H bonds, but suffer from poor chemoselectivity (see P. E. Gormisky, M. C. White, J. Am. Chem. Soc. 135, 14052-14055 (2013)). Certain enzymes, such as cytochrome P450s, form highly reactive metal oxos contained within elaborate active sites that enable exquisite control over chemoselectivity. However, the substrate-specificity often associated with enzymes precludes their use as a general synthetic method. A small molecule catalyst capable of chemoselectively oxidizing all types of C(sp3)-H bonds in preparative yields would revolutionize the synthesis and diversification of bioactive compounds.
Given the ubiquity of nitrogen functionality in bioactive compounds, its selective yet general introduction via C—H amination represents a particularly powerful synthetic strategy (J. L. Jeffrey, R. Sarpong, Chem. Sci. 4, 4092-4106 (2013)). Metallonitrene-based C—H amination is capable of functionalizing a broad range of C(sp3)-H bond types, but no single noble or base metal catalyst has yet successfully achieved a balance between reactivity and chemoselectivity. The extensively explored noble metal dirhodium carboxylate platform has resulted in catalysts that efficiently and stereospecifically functionalize robust 3o and 2o aliphatic C—H bonds via a concerted asynchronous C—H insertion mechanism (Roizen et al., Acc. Chem. Res. 45, 911-922 (2012)). However, these catalysts lack chemoselectivity, as direct oxidation of π-bonds competes with that of sp3 C—H bonds in olefin- and alkyne-containing substrates. Alternatively, small molecule iron catalysts access mechanistically distinct single electron pathways for nitrene transfer, affording orthogonal reactivity to rhodium catalysis (S. M. Paradine, M. C. White, J. Am. Chem. Soc. 134, 2036-2039 (2012)). As a result, these catalysts aminate allylic C—H bonds with high chemoselectivity over competing aziridination, but are only moderately reactive toward stronger aliphatic C—H bonds. This is a consequence of the allylic radicals accessed during C—H amination being energetically favored over aliphatic radicals that would be generated in aziridination or aliphatic C—H amination pathways. Additionally, there are no known metallonitrene-based catalysts capable of effectively aminating propargylic C—H bonds or very strong 1o aliphatic C—H bonds.
What is needed is a catalyst with high reactivity and high selectivity for C—H bonds, for example, to aminate benzylic, ethereal, 3o, 2o, and 1o aliphatic C—H bonds. Also needed are new catalysts and methods for preparing the synthetically important 1,3 amino alcohol motif.